The androgen receptor (AR) is a 110 Kda steroidal nuclear receptor. One of its key functions is androgen-activated gene transcription. The androgen receptor plays an important role in many male hormone related diseases such as prostate cancer, benign prostatic hypertrophy, male hair loss, muscle loss and hirsutism (hypertrichosis). For this reason, selective androgen receptor antagonists may be useful for such conditions and diseases including but not limited to: male contraception; treatment of a variety of male hormone-related conditions such as hypersexuality and sexual deviation; treatment of conditions including benign prostatic hyperplasia, acne vugaris, androgenetic alopecia, and hirsutism; preventing the symptoms associated with reduced testosterone such as hot flashes after castration; purposefully preventing or counteracting masculinisation in the case of transsexual women undergoing sex reassignment therapy; an antineoplastic agent and palliative, adjuvant or neoadjuvant hormonal therapy in prostate cancer; and decreasing the incidence of, halting or causing a regression of prostate cancer.
Prostate cancer is one of the most common cancers in men around the world, and is one of the leading causes of cancer death in men in the United States. Current standard treatment for local prostate cancer is surgery and radiation. Unfortunately, the cancer relapses in one-third of the treated patients. Together with patients diagnosed with advanced prostate cancer, they are treated with surgical castration or chemical castration, which is called hormone therapy (HT). Often HT is also combined with drugs acting as androgen receptor antagonists. Hormone therapy is highly effective for controlling cancer cells in most of patients with advanced prostate cancer. However, the prostate cancer cells eventually adapt to the low androgen environment and become resistant to HT. As a result, the cancer will recur in almost all such patients in 2-5 years.
Androgen receptor antagonist drugs, such as flutamide and bicalutamide, were originally designed to avoid the side effects of HT and to overcome resistance in prostate cancer patients. Although these androgen receptor antagonists work well as a co-treatment with HT in naïve advanced prostate cancer patients, their efficacy against refractory prostate cancer, as a single agent, or co-treatment, has been limited. There have been reports that androgen agonism was observed for hydroxyfluamide (the active form of flutamide) and bicalutamide. The residual agonistic effect may be responsible for the drugs' ineffectiveness in overcoming resistance. The therapeutic benefit of these androgen receptor antagonist drugs have also been hampered by significant side effects such as liver toxicities associated with flutamide and bicalutamide. Recent studies have suggested that reactivation of the AR signaling pathway may be the root cause for developing resistance to HT. Mutation and over-expression of AR are two of the common underlying molecular mechanisms for the observed resistance.
Therefore, there is significant medical need for better androgen receptor antagonists that should have potent antagonism but devoid of any agonism when treating castration resistant prostate cancer cells. There is also a need to reduce the observed side effects such as liver toxicity found in existing androgen receptor antagonist drugs.